• Christian Breunig, Bernadett J Mueller, Ludmila Umansky, Kristin Wahl, Katrin Hoffmann, Frank Lehner, Michael P Manns, Heike Bantel, and Christine S Falk.
• Authors' Affiliations: Division of Molecular Genome Analysis B050, German Cancer Research Center (DKFZ); Immunomonitoring Unit, National Center for Tumor Diseases (NCT) at the DKFZ; Department of Translational Immunology, DKFZ and NCT; Department of General, Visceral and Transplantation Surgery, University Hospital, Heidelberg; Institute of Transplant Immunology, OE8889, IFB-Tx; Departments of Gastroenterology, Hepatology and Endocrinology; and Abdominal and Transplantation Surgery, Hannover Medical School, Hannover, Germany.
• Clin Cancer Res. 2014 May 1; 20 (9): 2410-23.

PurposeSmall molecule inhibitors of the mitogen-activated protein kinase (MAPK) pathway, such as sorafenib, represent novel treatment options for advanced hepatocellular carcinoma. The aim of our study was to identify downstream targets as biomarker candidates that are directly linked to the oncogenic MAPK pathway in hepatocellular carcinoma and correlate with inhibition of this pathway by multikinase inhibitors.Experimental DesignHepatocellular carcinoma cell lines and fresh tumor and tumor-free liver tissues from patients with hepatocellular carcinoma were incubated with different BRaf or MEK inhibitors and analyzed for kinase phosphorylation, proliferation, induction of apoptosis, and chemokine secretion.ResultsHepatocellular carcinoma cell lines responded differentially to these inhibitors in a dose-dependent manner, even those targeting the same kinase. Sorafenib inhibited both MEK1 and ERK1/2 phosphorylation at high but increased signaling at low concentrations. Similarly, PLX4720 increased MEK/ERK signaling independently from mutations in BRaf or NRas. MEK inhibitors decreased ERK1/2 phosphorylation in a dose-dependent manner. These signaling characteristics correlated with inhibition of proliferation, induction of apoptosis, and chemokine secretion. Fresh tissues derived from patients diagnosed with primary hepatocellular carcinoma responded to these inhibitors with changes in their microenvironment following the patterns observed in hepatocellular carcinoma cells.ConclusionsOncogenic signaling of the MAPK pathway influences hepatocellular carcinoma sensitivity to treatment with BRaf and MEK inhibitors about cell fate independently from mutations in BRaf and NRas. MAPK inhibitors have a strong impact on chemokine secretion as a consequence of interference with oncogenic signaling. Therefore, novel biomarker candidates associated with the hepatocellular carcinoma microenvironment may be developed for prediction and monitoring of treatment response to small molecule inhibitors.©2014 AACR.

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